Phencyclidine and the midbrain dopamine system: electrophysiology and behavior

Area of Science:

• Neuroscience
• Pharmacology
• Neurochemistry

Background:

• Phencyclidine (PCP) is a dissociative anesthetic with known psychotomimetic effects.
• Its mechanism of action involves interaction with the N-methyl-D-aspartate (NMDA) receptor.
• Understanding PCP's effects on dopamine neurotransmission is crucial for elucidating its behavioral and abuse liability properties.

Purpose of the Study:

• To investigate the effects of phencyclidine (PCP) and related compounds on dopamine neuron activity in rats.
• To determine the role of NMDA receptor antagonism in PCP's neurochemical and behavioral effects.
• To assess the reinforcing properties of PCP and its congeners.

Main Methods:

• Extracellular recordings of A10 dopamine neurons in anesthetized rats.
• Administration of PCP, PCP-like drugs, and direct NMDA antagonists (CGS 19755, (+)CPP, NPC 12626).
• Midbrain slice electrophysiology to examine NMDA receptor-mediated excitations.
• Progressive-ratio self-administration paradigm to evaluate reinforcing efficacy.

Main Results:

• PCP and related drugs increased dopamine neuron firing and burst activity, correlating with NMDA antagonism.
• Direct NMDA antagonists did not alter dopamine neuron activity but attenuated PCP's effects.
• PCP did not activate dopamine neurons in midbrain slices but blocked NMDA-induced excitations.
• PCP and TCP showed less reinforcing efficacy than BTCP in self-administration tests.

Conclusions:

• PCP's excitation of dopamine neurons is mediated by noncompetitive NMDA receptor blockade.
• Differential affinity for dopamine reuptake and PCP binding sites influences reinforcing properties.
• PCP's psychotomimetic and abuse liability may stem from complex effects on dopamine neurotransmission.